Synthesis of l-Cladinose Using Enantioselective Desymmetrization

Abstract

l-Cladinose, a neutral sugar found in erythromycins and azithromycins, has been synthesized efficiently using enantioselective monobenzoylation of 2-propenylglycerol in the presence of the imine-CuCl₂ catalysts to elaborate the stereogenic quaternary center.

Key words

l-mycarose - l-cladinose - desymmetrization - quaternary centers - imine-CuCl₂

References and Notes

• 1 Johnson DA. Liu H.-w. In Comprehensive Chemistry of Natural Products Chemistry   Vol. 3:  Barton D. Nakanishi K. Meth-Cohn O. Pergamon; New York: 1999.  p.311-365  
• 2a Woodward RB. Angew. Chem.  1957,  69:  50 
• 2b Celmer WD. Pure Appl. Chem.  1971,  28:  413 
• 2c Omura S. Nakagawa A. J. Antibiot.  1975,  28:  401 
• 3a Martin JR. DeVault RL. Sinclair AC. Stanaszek RS. Johnson P. J. Antibiot.  1982,  35:  426 
• 3b Cevallos A. Guerriero A. J. Antibiot.  2003,  56:  280 
• 4a Hamill RH. Haney ME. Stamper MC. Wiley PF. Antibiot. Chemother.  1961,  11:  328 
• 4b Achenbach H. Regel W. Karl W. Chem. Ber.  1975,  108:  2481 
• 5a Grundy WE. Goldstein AW. Rickher C. Hanes ME. Warren HB. Sylvester JC. Antimicrob. Chemother.  1953,  3:  1215 
• 5b Sensi P. Greco A. Pagani H. Antibiot. Chemother.  1958,  8:  241 
• 6a Paul R. Tchelicheff S. Bull. Soc. Chim. Fr.  1957,  5:  443 
• 6b Paul R. Tchelicheff S. Bull. Soc. Chim. Fr.  1957,  5:  734 
• 6c Paul R. Tchelicheff S. Bull. Soc. Chim. Fr.  1960,  8:  150 
• 6d Omura S. Nakagawa A. Otani M. Hata T. Ogura H. Furuhata K. J. Am. Chem. Soc.  1969,  91:  3401 
• 7a Watanabe T. Nishida H. Satake K. Bull. Chem. Soc. Jpn.  1961,  34:  1285 
• 7b Watanabe T. Fujii T. Satake K. J. Biochem. (Tokyo)  1961,  50:  197 
• 7c Freiberg LA. Egan RS. Washburn WH. J. Org. Chem.  1974,  39:  2474 
• 8 Kawata S. Ashizawa S. Hirama M. J. Am. Chem. Soc.  1997,  119:  12012 
• 9 Lemal DM. Pacht PD. Woodward RB. Tetrahedron  1962,  18:  1275 
• 10a Flaherty B. Overend WG. Williams NR. J. Chem. Soc. C  1966,  398 
• 10b Howarth GB. Jones JKN. Can. J. Chem.  1967,  45:  2253 
• 10c Koft ER. Dorff P. Kullnig R. J. Org. Chem.  1989,  54:  2936 
• 10d Toshima K. Yoshida T. Mukaiyama S. Tatsuta K. Tetrahedron Lett.  1991,  32:  4139 
• 10e Lear MJ. Hirama M. Tetrahedron Lett.  1999,  40:  4897 
• 11 Montgomery SH. Pirrung MC. Heathcock CH. Carbohydr. Res.  1990,  32:  13 
• 12a Jung B. Kang SH. Proc. Natl. Acad. Sci. U. S. A.  2007,  104:  1471 
• 12b Jung B. Hong MS. Kang SH. Angew. Chem. Int. Ed.  2007,  46:  2616 
• 13a Bright GM. Nagel AA. Bordner J. Desai KA. Dibrino JN. Nowakowska J. Vincent L. Watrous RM. Sciavolino FC. English AR. Retsema JA. Anderson MR. Brennan LA. Borovoy RJ. Cimochowski CR. Faiella JA. Girard AE. Girard D. Herbert C. Manousos M. Mason R. J. Antibiot.  1988,  41:  1029 
• 13b Retsema JA. Girard AE. Schelkly W. Manousus M. Anderson MR. Bright GM. Borovoy RJ. Brennan LA. Mason R. Antimicrob. Agents Chemother.  1987,  31:  1939 
• 13c Kirst HA. Sides GD. Antimicrob. Agents Chemother.  1989,  33:  1419 
• 14 Hoppe D. Schmincke H. Kleemann H.-W. Tetrahedron  1989,  45:  687 
• 16 Tanaka S. Yamamoto H. Nozaki H. Sharpless KB. Michaelson RC. Cutting JD. J. Am. Chem. Soc.  1974,  96:  5254 
• 20a Woodward RB. Logusch E. Nambiar KP. Sakan K. Ward DE. Au-Yeung B.-W. Balaram P. Browne LJ. Card PJ. Chen CH. Chenevert RB. Fliri A. Frobel K. Gais H.-J. Garratt DG. Hayakawa K. Heggie W. Hesson DP. Hoppe D. Hoppe I. Hyatt JA. Ikeda D. Jacobi PA. Kim KS. Kobuke Y. Kojima K. Krowicki K. Lee VJ. Leutert T. Malchenko S. Martens J. Matthews RS. Ong BS. Press JB. Rajan Babu TV. Rousseau G. Sauter HM. Suzuki M. Tatsuta K. Tolbert LM. Truesdale EA. Uchida I. Ueda Y. Uyehara T. Vasella AT. Vladuchick WC. Wade PA. Williams RM. Wong HN.-C. J. Am. Chem. Soc.  1981,  103:  3210 
• 20b Woodward RB. Logusch E. Nambiar KP. Sakan K. Ward DE. Au-Yeung B.-W. Balaram P. Browne LJ. Card PJ. Chen CH. Chenevert RB. Fliri A. Frobel K. Gais H.-J. Garratt DG. Hayakawa K. Heggie W. Hesson DP. Hoppe D. Hoppe I. Hyatt JA. Ikeda D. Jacobi PA. Kim KS. Kobuke Y. Kojima K. Krowicki K. Lee VJ. Leutert T. Malchenko S. Martens J. Matthews RS. Ong BS. Press JB. Rajan Babu TV. Rousseau G. Sauter HM. Suzuki M. Tatsuta K. Tolbert LM. Truesdale EA. Uchida I. Ueda Y. Uyehara T. Vasella AT. Vladuchick WC. Wade PA. Williams RM. Wong HN.-C. J. Am. Chem. Soc.  1981,  103:  3213 
• 20c Woodward RB. Logusch E. Nambiar KP. Sakan K. Ward DE. Au-Yeung B.-W. Balaram P. Browne LJ. Card PJ. Chen CH. Chenevert RB. Fliri A. Frobel K. Gais H.-J. Garratt DG. Hayakawa K. Heggie W. Hesson DP. Hoppe D. Hoppe I. Hyatt JA. Ikeda D. Jacobi PA. Kim KS. Kobuke Y. Kojima K. Krowicki K. Lee VJ. Leutert T. Malchenko S. Martens J. Matthews RS. Ong BS. Press JB. Rajan Babu TV. Rousseau G. Sauter HM. Suzuki M. Tatsuta K. Tolbert LM. Truesdale EA. Uchida I. Ueda Y. Uyehara T. Vasella AT. Vladuchick WC. Wade PA. Williams RM. Wong HN.-C. J. Am. Chem. Soc.  1981,  103:  3215 

15

Compound 12: ^¹H NMR (400 MHz, CDCl₃): δ = 1.26 (s, 3 H), 1.64 (br s, 1 H), 1.70 (d, J = 5.2 Hz, 3 H), 2.11-2.48 (m, 2 H), 5.07-5.21 (m, 2 H), 5.59 (d, J = 14.0 Hz, 1 H), 5.71-5.92 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.6, 27.7, 47.2, 71.8, 118.7, 122.9, 133.9, 137.6. HRMS (EI): m/z calcd for C₈H₁₄O: 126.1044; found: 126.1041.

17

Synthesis of Epoxide 14 Vanadyl(acetylacetonate) (25 mg, 0.095 mmol) and
t-BuO₂H (2.0 M in CH₂Cl₂, 2.38 mL, 4.76 mmol) were added to diene 12 (400 mg, 3.17 mmol) in CH₂Cl₂ (3 mL) at 0 ˚C in sequence. The mixture was stirred at 0 ˚C for 30 min and then at r.t. for 6 h. After quenching the excess peroxide with 10% aq Na₂S₂O₃ (10 mL), the following extraction with EtOAc (3 × 5 mL), drying over MgSO₄ (500 mg), filtration and evaporation under reduced pressure gave the crude product, which was separated by column chromatography (SiO₂, 230-400 mesh, EtOAc-hexane, 1:3) to furnish the desired epoxide (374 mg, 83%) along with the regioisomeric epoxide (35 mg, 7%). Sodium hydride (60% dispersion in mineral oil, 126 mg, 3.16 mmol) was added to the disubstituted epoxide (374 mg, 2.63 mmol) in THF (3 mL) at 0 ˚C portionwise. To the generated alkoxide was injected MeI (0.25 mL, 4.0 mmol), and the resulting solution was stirred at 0 ˚C for 15 min and then at r.t. for 3 h. After quenching the methylation with sat. NH₄Cl (3 mL), the workup was done by extraction with EtOAc (3 × 4 mL), drying with MgSO₄ (300 mg), filtration and evaporation in vacuo. The residual material was purified chromato-graphically (SiO₂, 230-400 mesh, EtOAc-hexane, 1:4) to render the epoxy methyl ether 14 (329 mg, 80%).
Compound 14: ^¹H NMR (400 MHz, CDCl₃): δ = 1.21 (s, 3 H), 1.33 (d, J = 5.2 Hz, 3 H), 1.91-2.10 (m, 2 H), 2.71 (d, J = 2.3 Hz, 1 H), 3.12 (qd, J = 5.2, 2.3 Hz, 1 H), 3.31 (s, 3 H), 5.10-5.25 (m, 2 H), 5.78-5.94 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.3, 25.1, 39.1, 51.5, 52.6, 62.4, 63.5, 118.1, 133.6. HRMS (EI): m/z calcd for C₉H₁₆O₂: 156.1150; found: 156.1145.

18

Synthesis of Lactone 15
To epoxide 14 (300mg, 1.92 mmol), dissolved in a mixture of CH₂Cl₂ (4 mL), MeCN (4 mL), and H₂O (6 mL), were added NaIO₄ (1.68 g, 7.87 mmol) and RuCl₃˙3H₂O (16 mg) sequentially at r.t., and the mixture was stirred at that temperature for 8 h. After addition of CH₂Cl₂ (50 mL) to the mixture, the resulting solution was washed with aq HCl (1.0 M, 30 mL) twice and then brine (20 mL) once. The remaining organic layer was dried over MgSO₄ (1 g), filtered and evaporated in vacuo. The residue was purified by column chromatography (SiO₂, 230-400 mesh, EtOAc-hexane, 1:2) to give the corresponding carboxylic acid (267 mg, 80%). The carboxylic acid (267 mg, 1.53 mmol) in CH₂Cl₂ (4 mL) was stirred in the presence of BF₃˙OEt₂ (58 µL, 0.46 mmol) at 0 ˚C for 10 min and then at r.t. for 5 h. After addition of H₂O (3 mL), the resulting solution was extracted with EtOAc (3 × 5 mL), the organic layer was dried over MgSO₄ (400 mg), filtered and evaporated in vacuo. The residue was separated by column chromatography (SiO₂, 230-400 mesh, EtOAc-hexane, 1:2) to afford the lactone 15 (229 mg, 86%).
Compound 15: ^¹H NMR (400 MHz, CDCl₃): δ = 1.28 (d, J = 6.3 Hz, 3 H), 1.42 (s, 3 H), 2.52 (d, J = 17.1 Hz, 1 H), 2.66 (d, J = 17.1 Hz, 1 H), 3.24 (s, 3 H), 3.88-3.95 (m, 1 H), 4.06 (d, J = 7.1 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.6, 20.4, 41.5, 51.1, 66.5, 80.6, 87.9, 174.0. HRMS (EI): m/z calcd for C₈H₁₄O₄: 174.0892; found: 174.0889.

19

Synthesis of l -Cladinose (2) Diisobutylaluminum hydride (1.0 M in THF, 2.87 mL, 2.87 mmol) was added to 15 (200 mg, 1.15 mmol) in THF (5 mL) dropwise at -78 ˚C and the resulting mixture was stirred at that temperature for 3 h. The reaction was quenched with a 4:1 mixture of MeOH and H₂O at -78 ˚C, and then the temperature was raised to r.t. After addition of sat. NaHCO₃ (0.5 mL) and MgSO₄ (200 mg) to the mixture, it was filtered using EtOAc (10 mL), and the organic layer was evaporated in vacuo. The remaining residue was purified by column chromatography (SiO₂, 230-400 mesh, EtOAc-hexane, 1:1) to deliver l-cladinose (2, 164 mg, 81%).